Hydroxy-acid cosmetics

ABSTRACT

A method for alleviating the symptoms of a cosmetic or dermatologic skin condition is described. An effective amount of a poly(hydroxy acid)/polymer conjugate in a pharmaceutically or cosmetically acceptable vehicle is provided. Topical compositions of the conjugates with another cosmetic or dermatological agent, and compounds of the conjugates having attached physiologically active functional groups, are also provided.

BACKGROUND OF THE INVENTION

This invention relates to poly(hydroxy acid)/polymer conjugateformulations for cosmetic and dermatological skin applications, andmethods of use thereof.

Skin disorders range from various cosmetic conditions to severedermatologic diseases. Conventional treatments for many of thesedisorders have included topical applications of oils, emollients,humectants, drugs and medicaments. Such treatments have met with varyingdegrees of success.

It is also known to use hydroxy acids, especially alpha and beta hydroxyacids, in the treatment of various skin conditions, for example, asreviewed in U.S. Pat. Nos. 5,091,171 and 4,363,815 to Yu and Van Scott,which describe the use of various hydroxy acid monomers and oligomers(containing two or three units) in skin treatment. Other patentsrelating to skin treatment with hydroxy acids include U.S. Pat. Nos.3,988,470, 4,105,782, 4,234,599, 4,380,549, and 5,258,391. Othersdescribing the use of hydroxy acids in skin treatment include EP 0 358528 by Periera, U.S. Pat. No. 4,294,852 to Wildnauer et al., and U.S.Pat. No. 2,726,982 to Ochs.

While hydroxy acids are well-known in skin treatment, there are variousproblems inherent in their application to skin, especially from thepoint of view of safety. In particular, use of a formulation whichcontain free monomeric hydroxy acids results in an immediate one-timeintroduction of the full dosage upon application to the skin, which cancause peeling, chemical burning and even scarring of the skin. Thisproblem is specially acute with the more concentrated doses described inthe Yu et al patents, referred to above.

In principle, this problem can be overcome by polymerization of thehydroxy acids (HAs) to form polyhydroxy acids (PHAs). Polyhydroxy acidssuch as polylactic acid, polyglycolic acid, are polycaprolactone arewell-known in the manufacture of degradable medical devices, such assutures (for example, Vicryl®), absorbable sponges and fabrics, andother devices. They are suitable for such uses because PHAs becomewater-insoluble at relatively low degrees of polymerization. Thepolyhydroxy acids gradually degrade back to the monomeric acids in thepresence of water or of bodily fluids at approximately neutral pH. Theprincipal drawback of these materials is a mild degree of irritation orinflammation at the site during the degradation of the polymer. This isacceptable in the context of wound repair, but is less acceptable intreatment of the skin for relief of cosmetic problems.

Moreover, it is difficult to eliminate this effect by dissolving ordispersing the PHAs in solvent. It is known that polyhydroxy acids suchas polyglycolic acid are not soluble in skin-compatible solvents, butonly in organic solvents such as hexafluoroacetone hexahydrate orhexafluoroisopropanol, acetone, and methylene chloride. Attempts todisperse pure PHAs in other components of a cosmetic formulation arethus difficult, and could lead to phase separation of a PHA-rich phasewithin the formulation, leading to gradations of differentconcentrations of the hydroxy acid on the skin to which the formulationis applied.

It is therefore an object of the invention to provide a safe, effectiveand easy method for alleviating the symptoms of a cosmetic ordermatologic skin condition.

It is a further object of the invention to provide a method for thecontrolled release of hydroxy acids onto the skin of a person toalleviate the symptoms of a cosmetic or dermatologic skin condition.

It is another object of the invention to provide a method foralleviating the symptoms of a cosmetic or dermatologic skin conditionwhich combines the advantages of a humectant and an hydroxy acid.

It is a still further object of the invention to provide a method foralleviating the symptoms of a cosmetic or dermatologic skin condition byproviding a formulation which results in substantially uniformapplication of hydroxy acids to the skin.

SUMMARY OF THE INVENTION

A method for alleviating the symptoms of a cosmetic or dermatologic skincondition is provided wherein an effective amount of a poly(hydroxyacid)/polymer conjugate in a pharmaceutically or cosmetically acceptablevehicle is topically applied to the skin. Vehicles include powders,lotions, gels, sprays, sticks, creams, ointments, liquids, emulsions,foams and aerosols. The conjugate consists of a backbone polymer havingpoly(hydroxy acids) or derivatives thereof coupled to the backbone toform a brush, linear or branched copolymer. Selection of the backbonecan be used to impart desirable properties, as well as control the rateof degradation, and, in turn, the rate of release of hydroxy acids tothe skin.

The conjugates can also be used as a method for delivering to the skin aphysiologically active functional group, such as a fragrance, ananti-microbial such as a bactericide or fungicide, acne medication, wartremover such as salicylic acid with or without other hydroxy acids, areductant to bleach skin spots such as hydroxyquinone, a nutrient suchas vitamin A or other vitamins, and sunscreens.

DETAILED DESCRIPTION OF THE INVENTION

A method for alleviating the symptoms of a cosmetic or dermatologic skincondition has been developed in which an effective amount of apoly(hydroxy acid)/polymer conjugate in a pharmaceutically orcosmetically acceptable vehicle is topically applied to the skin.

Applications

As used herein, compositions referred to for cosmetic use, skinapplication, or topical use, encompass treatments and uses which arespecifically medicinal as well as conventional cosmetic uses such as inbeauty aids and toiletries.

By skin conditions is meant any skin condition whose symptoms can bealleviated by the poly(hydroxy acid)/polymer conjugates describedherein. Examples of skin conditions include dry skin, xerosis,ichthyosis, dandruff, brownish spots, keratoses, melasma, lentigines,age spots, liver spots, pigmented spots, blemishes, wrinkles, skinlines, fine lines, oily skin, ache, warts, eczema, pruritic skin,psoriasis, inflammatory dermatoses, disturbed keratinization, skinchanges associated with aging, nail or skin requiring cleansers,conditioners or treatment, and hair or scalp requiring shampooing orconditioning.

Additional uses are associated with application to the skin ofantibiotics, antifungals, pediculicides, antiperspirants, antipruritics,analgesics, anesthetics, treatments for blisters, canker sores, insectbites and diaper rash, insect repellents and sunscreens. Preferred usesof the conjugate are for dry skin or wrinkles.

Polymeric Conjugates

As discussed above, the hydroxy acids typically used in medicinal andcosmetic applications are hydroxy acid monomers or polymers of hydroxyacids. In contrast, as described herein, hydroxy acid conjugates orcopolymers have now been found to be advantageous, due to a more definedrelease rate and avoidance of concentration gradients.

The poly(hydroxy acid)/polymer conjugate may be represented by theformula

    PaHb

where P is a polymer block having monomer subunits M, in which themonomer subunits are the same or different, and a plurality of which arenot hydroxy acids; H is a poly(hydroxy acid) block; and a and b areintegers of one or more and denote the number of P and of H blocks inthe copolymer. The P blocks and H blocks can be joined in any convenientarrangement. Simple linear arrangements are contemplated, in which theblocks are joined P-H, P-H-P, or H-P-H. The last arrangement, which is apreferred embodiment, is readily made by polymerizing monomeric ordimeric hydroxy acid derivatives, such as lactide, glycolide, orcaprolactone, onto a dihydroxy terminated compound such as apolyethylene glycol. Other arrangements of P and H include starcopolymers or brush copolymers in which multiple H blocks are dependentfrom a single P chain, P-Hb where b is greater than 2. The alternative,PaH, where a is greater than two, is generally less preferable, but ispossible if one or more of the hydroxy acids comprising block H containsmore than one hydroxyl group, as with glyceric acid. Further, the P andH blocks can alternate in a larger polymer, which can be linear orbranched--for example, PHPHPH . . . . If a polymer of this sort isdesired, it can be made by forming a symmetrical H block by polymerizinga hydroxy acid onto a divalent or multivalent initiator, such asethylene glycol, glycerol, or erythritol. The resulting H blocks can becrosslinked with an activated P group, for example,isocyanate-terminated polyethylene glycol, to form copolymers useful inthe invention.

The monomer subunits of either polymer are most typically in a lineararrangement, but may also be branched. The polymer P may itself be ablock, graft or brush copolymer of other polymeric ingredients, theplurality of which are not polyhydroxy acid polymers. P has a totalmolecular weight of from about 200 to about 200,000 Daltons, preferablyfrom about 400 to 50,000 Daltons, and more preferably from about 500 toabout 25,000 Daltons. P has at least one reactive group onto which Hblocks can be polymerized or grafted. Any sufficiently reactive group issuitable. Examples of reactive groups are hydroxyl, carboxyl, amine,imine, amide, azide, sulfide, sulfhydryl, sulfate, sulfonate, phosphate,halogen, ester, phenol, acetal, hemiacetal, isocyanate, cyanate, allyl,vinyl, acrylyl, nitro, nitrile, and aldehyde. Other examples of suitablereactive groups will be apparent to those skilled in the art. Preferredreactive groups are hydroxyl, carboxyl, and amine. Hydroxyl is mostpreferred.

The reactive groups may have their reactivity further enhanced byderivatization with activation reagents appropriate to the chemistry ofthe group. These are well known in the art; illustrative examplesinclude carbodiimides for activation of carboxyl or amine groups;bisulfites for stabilizing aldehyde groups; aryl disulfide reagents asleaving groups for sulfhydryls; phosgene for amines, alcohols, andphenols; and di-isocyanates for hydroxyls, amines or carboxyls.

The weight fraction of the poly(hydroxy acid) blocks in the poly(hydroxyacid)/polymer conjugate can range from about 1% to as high as at leastabout 60% by weight, preferably in the range of about 2% to about 40%,and more preferably in the range of about 3% to about 25%. Lowerconcentrations of hydroxy acid groups will make the conjugate morewater-soluble and more easily dispersible; higher concentrations may bemore effective per unit weight. The detailed choice of weightconcentration of hydroxy acids in the composition will be dictated inpart by the exact end use of the conjugate.

The total molecular weight of the conjugate (of poly(hydroxy acid) withbackbone polymer) is not critical, and can be varied from about 300 D toover 300,000 D. More typical molecular weights are from about 500 to100,000 D, and in most instances conjugate molecules of from about 1000to 50,000 D are employed. The viscosity of the polymer is important ingiving a cosmetic or therapeutic composition with the correctspreadability and feel for the particular use, and can be controlled byselecting the molecular weight and the relative proportion of theblocks, using established principles.

Backbone Polymers

P may be any polymer which, when grafted or otherwise bonded with Hblocks, gives the properties desired in a cosmetic ingredient. Thesequalities include humectancy; dispersability in cosmetic baseingredients (such as lotions), or ready spreadability on the skin; andnon-irritancy of the skin by the polymer P, which may remain on the skinafter the hydroxy acids have been liberated to have their effect. Sincepolymeric hydroxy acids generally have low humectancy, it is desirablethat P be a humectant, which implies that P is preferably hydrophilic.Moreover, it is highly preferable that P be a polymer which is approvedor Generally Recognized as Safe for application to the skin. Individualexamples and lists of such polymers may be found in the literature; inparticular, the Cosmetics, Fragrance and Toiletries Dictionary listsmost ingredients commonly used in cosmetic formulations. Approved usesof potential cosmetic ingredients can be found in the Merck Index.

Illustrative examples of P include polyethylene oxide (PEG), also knownas polyethylene glycol or polyoxyethylene; polypropylene oxide;copolymers of polyethylene oxide with other alkylene oxides,particularly as block copolymers of PEG and polypropylene oxide orpolybutylene oxide (known as Pluronics, Tetronics, or Butyronics,available from BASF); other single-component and mixed polyalkyleneoxides; polyvinyl alcohol and partially hydrolyzed polyvinyl acetate;polyvinyl pyrrolidone (Povidone); poylethyloxazoline; polyethyleneimine;polymers based on (meth) acrylates (i.e., acrylates, methacrylates andcopolymers thereof), including (meth) acrylic acid, (meth) acrylamides,hydroxyethyl (meth) acrylates such as HEMA, other carboxyl-substituted(meth) acrylate derivatives, copolymers of these, and copolymers ofthese with other ethylenically unsaturated monomers, including ethylene,maleic acid or maleic anhydride, styrene, and fumaric acid; mixedcopolymers of the monomers of the above materials, for examplepoly(ethylene-vinyl acetate)(EVAC).

Suitable natural or semi-synthetic polymers include polysaccharides suchas starch, cellulose, derivatized celluloses (including hydroxyethylcellulose, methyl hydroxypropyl cellulose, carboxymethyl cellulose anddiethylaminoethyl cellulose), dextran and dextran sulfate, levulan,chitin and chitosan, xanthan, galactomannans such as locust bean gum,gellan, xanthan, schizophyllan, agar, agarose, hydroxyethyl agarose,carrageenan, alginate and propylene glycol alginate, konjac glucomannan,locust bean gum (carob flour), guar, pullulan, schizophyllan, dextrins,maltodextrins, and starches; heparin and related polysaccharides;glycosoaminoglycans such as hyaluronic acid; nucleic acids including DNAand RNA; proteins including gelatin, collagen, albumin, ovalbumin andpolyamino acids; peptides; lipids including fatty acids, steroids,phospholipids, lysolipids and fatty acid dimers; and polyphenols, suchas tannins; or combinations thereof. In certain embodiments,glycosoaminoglycans other than deacetylated hyaluronic acid are used.

Preferably, P is PEG (polyethylene glycol or polyethylene oxide),polyalkylene oxide, polyvinyl alcohol, polyacrylic derivatives, dextran,hydroxyethylcellulose, starch or combinations thereof. Most preferably,P is PEG (polyethylene glycol or polyethylene oxide). Among thecharacteristics that make PEG a preferred polymer are its highhydrophilicity and water solubility, its humectancy, and its excellentbiocompatibility.

In certain embodiments, P is a non-amphoteric or non-pseudoamphotericpolymer. By amphoteric is meant a substance that behaves either as anacid or a base, and can be an organic or an inorganic compound. Themolecule of an organic amphoteric compound consists of at least onebasic and one acidic group. The basic groups include amino, imino andguanido groups. The acidic groups include carboxylic, phosphoric andsulfonic groups. Inorganic amphoteric compounds include certain metallicoxides such as aluminum oxide and zinc oxide. By pseudoamphotericcompounds are meant compounds that are either structurally related totrue amphoteric compounds or capable of inducing the same function whenthey are incorporated into the compositions containing poly(hydroxyacids).

Hydroxy Acids

H represents a block consisting substantially, predominantly or entirelyof hydroxy acid monomers. H is preferably formed by the condensation ofn hydroxy acid subunits A; H can also be described as A_(n). Thelinkages between the hydroxy acid subunits in H will typically beesters. Each of the n hydroxy acid subunits in a given H block may bethe same or different. It will typically more convenient in synthesis tomake each of the H blocks substantially identical to the other H blocksin composition and length, within the limitation of the statisticalnature of many polymerization processes, which will produce randomvariations about a mean of composition and of chain length.

The number of H blocks in the copolymer is b, which is an integer atleast equal to 1, preferably 1 to about 100, more preferably 2 to about50 or 4 to about 80 depending on application. Larger values of b mayrequire that the values of n, described next, are towards the lower endof the range for n in order to retain the desired balance of activity,spreadability and humectancy.

Hydroxy acids are organic molecules containing at least one carboxylicacid function and at least one hydroxyl group in addition to thecarboxyl. Typical hydroxy acids are lactic, glycolic, glyceric andsalicylic; as described herein, carbonic acid is defined as an hydroxyacid. Any hydroxy acid which alleviates the symptoms of a cosmetic ordermatologic skin condition can be used. The hydroxy acid can be analpha, beta, gamma, delta, epsilon or omega hydroxy acid.

Preferred hydroxy acids are any small organic molecule of monomermolecular weight less than about 400 daltons which contains at least onehydroxyl group and at least one carboxyl group. More preferred hydroxyacids contain only one of either a hydroxyl or carboxyl group. Mostpreferred hydroxy acids contain one hydroxyl and one carboxyl group,such as normal alkanes or alkenes derivatized at the 1-position to forma carboxyl group, and substituted at a carbon atom numbered 2 or greaterwith an hydroxyl group. Hydroxy acid is also meant to include carbonicacid, which is similar to a 1-hydroxy carboxylic acid. It is preferablethat the hydroxy acids contain no amine, sulfur, or other reactivegroup, besides hydroxyl or carboxyl, unless such other reactive group isblocked or protected.

The hydroxy acid subunits A have the formula (HO)RC(═O)OH, where R isselected from a covalent bond and an alkyl (normal, branched or cyclic),alkenyl or aryl group having from 1 to 25 carbon atoms, preferably 1 to10, most preferably 1 to 6. R may be further substituted by additionalgroups, selected from hydroxyl, carboxyl, amide, lower alkyl mono-anddi-amide, lower alkyl ester, halogen, sulfate, sulfonate and phosphate,where lower alkyl is a linear or branched alkane or alkene with 1 to 6carbons and may also contain up to two hydroxyl groups. The additionalgroups may be connected to R through an ether linkage. It should benoted that under this formula carbonic acid is defined as a hydroxyacid. The obligatory OH (hydroxyl) is joined to the R at any carbon ofthe R, but preferably at the alpha (or 2-), beta (or 3-) or gamma (4-)positions with respect to the carboxyl. Preferred hydroxy acids arelactic, glycolic, hydroxybutyric, hydroxycaproic and salicylic.

The A subunits are preferably joined by ester linkages. When thesubunits each have only one carboxyl and one hydroxyl, the An (i.e., H)block can be represented as

    Q--(--RC(═O)O--).sub.n-1 RC(═O)--S

where one of Q and S is a covalent linkage to the backbone polymer P,and the other is selected from a hydroxyl group, a carboxyl group, or alower alkyl (as defined above) ether or ester, or a polymerizable groupor a physiologically active functional group, or a covalent linkage tothe same or another backbone polymer P; and where each of the R groupsis an R as defined above, and each of the R groups may be the same ordifferent. When one or more of the R contains hydroxyl or carboxylgroups, then the hydroxy acid polymer block An may be branched.

Other linkages may be used besides the ester linkage, as long as thelinkage confers the property of slow spontaneous hydrolysis in thepresence of water on the linkage. In the particular case when R is acovalent bond, it is convenient to polymerize a cyclic carbonate, suchas trimethylenecarbonate, to form a polymer

    HOC(═O)OC.sub.3 H.sub.6 OC(═O)O . . . C(═O)OH,

which can be considered as the copolymer of "1-hydroxy carboxylic acid"(carbonic acid) and propane 1,3-diol. Thus, the hydroxy acids may belinked by dihydroxy lower alkyl groups, particularly when R is acovalent bond.

In synthesis of the poly(hydroxy acids), various forms of the hydroxyacids can be used for the polymerization, including free acids, salts,anhydrides or lactones. Preferably, lactones are used, such as thedimeric ring lactones (lactide or glycolide), or lactones such ascaprolactone, valerolactone, or butyrolactone.

Lists of potentially suitable hydroxy acids can be found in theliterature, for example in various patents by Yu and van Scott. Examplesof alkyl alpha hydroxy acids include 2-hydroxyethanoic acid (glycolicacid), 2-hydroxypropanoic acid (lactic acid), 2-methyl2-hydroxypropanoic acid (methyl lactic acid), 2-hydroxybutanoic acid,2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoicacid, 2-hydroxyoctanoic acid, 2-hydroxynonanoic acid, 2-hydroxydecanoicacid, 2-hydroxyundecanoic acid, 2-hydroxydodecanoic acid (alphahydroxylauric acid), 2-hydroxytetradecanoic acid (alpha hydroxymyristicacid), 2-hydroxyhexadecanoic acid (alpha hydroxypalmitic acid),2-hydroxyoctadecanoic acid (alpha hydroxystearic acid) and2-hydroxyeicosanoic acid (alpha hydroxyarachidonic acid). Preferredalpha hydroxy acids are glycolic acid and lactic acid.

Examples of aralkyl or aryl alpha hydroxy acids include 2-phenyl2-hydroxyethanoic acid (mandelic acid), 2,2-diphenyl 2-hydroxyethanoicacid (benzilic acid), 3-phenyl 2-hydroxypropanoic acid (phenyllacticacid), 2-phenyl 2-methyl 2-hydroxyethanoic acid (atrolactic acid),2-(4'-hydroxyphenyl) 2-hydroxyethanoic acid, 2-(4'-chlorophenyl)2-hydroxyethanoic acid, 2-(3'-hydroxy-4'-methoxyphenyl)2-hydroxyethanoic acid, 2-(4'-hydroxy-3'-methoxyphenyl)2-hydroxyethanoic acid, 3-(2'-hydroxyphenyl) 2-hydroxypropanoic acid,3-(4'-hydroxyphenyl) 2-hydroxypropanoic and 2-(3',4'-dihydroxyphenyl)2-hydroxyethanoic acid.

Examples of poly(alpha hydroxy acids) include 2,3-dihydroxypropanoicacid (glyceric acid), 2,3,4-trihydroxybutanoic acid (isomers; erythronicacid, threonic acid), 2,3,4,5-tetrahydroxypentanoic acid (isomers;ribonic acid, arabinoic acid, xylonic acid, lyxonic acid),2,3,4,5,6-pentahydroxyhexanoic acid, (isomers; allonic acid, altronicacid, gluconic acid, mannoic acid, gulonic acid, idonic acid, galactonicacid, talonic acid), 2,3,4,5,6,7-hexahydroxyheptanoic acid (isomers;glucoheptonic acid, galactoheptonic acid), 2-hydroxypropane-1,3-dioicacid (tartronic acid), 2-hydroxybutane-1,4-dioic acid (malic acid),2,3-dihydroxybutane-1,4-dioic acid (tartaric acid),2-hydroxy-2-carboxypentane-1,5-dioic acid (citric acid),2,3,4,5-tetrahydroxyhexane-1,6-dioic acid (isomers; saccharic acid,mucic acid). Cyclic hydroxy acids such as salicylic acid and appropriatederivatives can also be used in the conjugates.

Examples of beta hydroxy acids which can form the poly(hydroxy acid)units include hydracrylic acid, 3-hydroxy butyric acid, 3-hydroxypentanoic acid and 3-hydroxy caproic acid. Preferred beta hydroxy acidsare 3-hydroxy-1-alkanoic acids where the alkane is selected from alkaneshaving about 3 to about 25 carbon atoms, preferably about 3 to about 6carbon atoms. Salicylic acid may also be considered a beta hydroxy acid.

Examples of gamma hydroxy acids which can form the poly(hydroxy acid)units include 4-hydroxy butyric acid, 4-hydroxy valeric acid (4-hydroxypentanoic acid), 4-hydroxy isovaleric acid, 4-hydroxy caproic acid, and4-hydroxy substituted derivatives of higher fatty acids. 4-hydroxybutyric acid, preferably in the lactone form in the poly(hydroxy acid)unit, is preferred. Examples of delta hydroxy acids include 5-hydroxypentanoic acid, 5-hydroxy caproic acid, and 5-hydroxy substitutedderivatives of higher fatty acids. An example of an epsilon hydroxy acidis 6-hydroxycaproic acid, preferably in the lactone form (commonly knownas caprolactone), and 6-hydroxy substituted derivatives of higher fattyacids in the poly(hydroxy acid) unit. Further examples of gamma andhigher hydroxy acids can be constructed, as known by those skilled inthe art, by using the alpha or beta hydroxy acids listed above, adding agamma or higher hydroxy (if not already present) to a gamma or highercarbon if present, and deleting any alpha or beta hydroxyls as required.Hydroxy derivatives of common fatty acids, such as 9- or 10-hydroxyderivatives of oleic, linoleic or linolenic acids, may also be used.

Polyhydroxy monocarboxylic acids which maybe polymerized into blocks inthe conjugates described herein include glyceric, dihydroxybutyric,ascorbic and glucuronic, mannuronic and other hexose and penrose acids.Other suitable hydroxy acids include those containing more than onecarboxyl group and at least one hydroxyl, including but not limited totartronic, hydroxymalonic, malic, citramalic, hydroxyglutaric, tartaric,hydroxyfumaric, hydroxymaleic, dihydroxy maleic, dihydroxy fumaric,dihydroxy tartaric, citric and isocitric.

The poly(hydroxy acids) can be present as pure species, enantiomericmixtures, or mixtures of different acids. It is preferable that at leasta portion, for example, about 5% to about 10%, of the hydroxy acids arealpha or beta hydroxy acids. Preferably, the proportion is about 10% toabout 20%, more preferably it is about 20% to about 50%, and mostpreferably about 50% or more, on a molar basis, of the hydroxy acidmonomers present in the poly(hydroxy acid)/polymer conjugate.

The Conjugate

The H or A_(n) poly(hydroxy acid) block is attached to the P polymer togive a poly(hydroxy acid)/polymer conjugate. Preferably, the attachmentis a covalent linkage. The particular linkage can be any linkage thatpreserves the activity of the hydroxy acid. Preferably, such linkagesresult from reactions with the hydroxy or carboxy termini of thepoly(hydroxy acids). Preferred groups on the polymer are hydroxy,carboxy and amine. Examples of linkages include esters, amides,anhydrides, acetals, hydroxamates, carbonates and ureas, and others asnoted above. Preferred linkages are esters and amides. Methods ofsynthesizing these linkages are well known to those skilled in the art.Such methods can be found, for example, in textbooks of syntheticorganic chemistry, compendia such as Beilstein (Beilstein Handbook ofOrganic Chemistry, pub. Springer-Verlag, Berlin; multivolume.) and"Fieser and Fieser's Reagents for Organic Chemistry" (John Wiley, N.Y.;multivolume).

For reactions in which the polymer backbone is polyethylene glycol, thearticle by Harris, J. M., Rev. Macromol. Chem. Phys. C25(3):325-373(1985), is useful. Specific examples of syntheses are illustrated in theExamples below. Preferably, the linkages are hydrolysable in water.Degradation then takes place through the hydrolysis of the linkage,releasing the polymer and the hydroxy acid and its oligomers. As usedherein, "degradable" or "biodegradable" refers to spontaneous hydrolysisin the presence of skin or bodily fluids within a finite and predictableperiod of less than one year. Preferable degradation times are shorter,of the order of months, weeks, and more preferably days or hours.

Block copolymers are known in which poly(hydroxy acid) blocks areattached to backbone polymers. These copolymers will gradually degradeon exposure to water, liberating monomeric hydroxy acid and the originalbackbone polymer. For example, copolymers containing blocks ofpolymerized hydroxy acids (PHA) conjugated to PEG (polyethylene glycol,also called polyethylene oxide or polyoxyethylene) are described in U.S.Pat. No. 2,917,410 to Vitalis, for treatment of textile yarns to impartlubricity. U.S. Pat. No. 3,689,531 to Critchfield, et. al. describeplastics made by copolymerization of hydroxy acids with other monomers.U.S. Pat. No. 3,784,585 to Schmitt, et. al. describes PGA (polyglycolicacid) conjugates with various polymers for rendering plasticsbiodegradable. U.S. Pat. No. 4,857,602 to Casey, et. al. and U.S. Pat.No. 5,312,437 to Hermes, et. al. described PEG-PHA (polyethyleneoxide-polyhydroxy acid) conjugates for lubrication of sutures.

U.S. Pat. No. 4,882,168 to Casey, et. al. and U.S. Pat. No. 4,526,938 toChurchill, et. al. use PEG-PHA type copolymers for drug delivery. U.S.Pat. No. 4,563,489 to Urist uses unconjugated polylactic acid for drugdelivery. U.S. Pat. No. 4,826,945 to Cohn, et. al. describes PEG-PHAconjugates to make absorbable sutures. U.S. Pat. No. 4,942,035 toChurchill, et. al. describe conjugates of PHA with PVA (polyvinylalcohol). WO 93/17669 by the University of Texas describe blockcopolymers of PHAs with various non-ionic backbone polymers, includingPEGs of various molecular weights, other polyalkylene oxides and mixedpolyalkylene oxides (such as Pluronics®, poloxamers and Tetronics™),PVA, poly(ethylene vinylacetate), polyvinylpyrrolidone, dextran, andsoluble derivatives of cellulose (such as hydroxyethyl cellulose). Theseare used as intermediates in the manufacture of photoreactive gellingmacromers for use in adhesion prevention and other internal medicalconditions responsive to the application of biodegradable gel barriers.These copolymers are soluble in water; by varying the backbone,solubility in other skin-compatible solvents can be obtained.

All of these publications, the teachings of which are incorporatedherein by reference, teach methods for making such block copolymers.Methods for conjugating additional groups to the backbone polymer or thePHA/backbone copolymer are also disclosed by WO 93/17669 by theUniversity of Texas and by others, including WO 93/24476 by CloverConsolidated and Zalipsky, et. al., Eur. Polymer J. 19, 1177-1183,(1983).

The use of polyethylene glycols in cosmetics is well known; see, forexample, U.S. Pat. No. 4,668,430 to Schmolkka, or U.S. Pat. No.4,883,660 to Blackman et al. The use of more exotic ingredients, such ashyaluronic acid and deoxyribonucleic acid, is also described in U.S.Pat. No. 5,194,253 to Garrido.

In certain embodiments, one or more of the attached poly(hydroxy acid)units is capped with a polymerizable group attached to the terminus ofthe poly(hydroxy acid). "Polymerizable" means that the group has thecapacity to form additional covalent bonds resulting in cross-linkingbetween individual poly(hydroxy acid)/polymer conjugates. Suchcross-linking can result in the formation of a gel, for example, ahydrogel. Examples of suitable polymerizable groups include smallmolecules with double and triple bonds, such as acrylates, (meth)acrylates, fumaric acid, maleic acid, itaconic acid, allyl groups, vinylgroups, acetylenic groups, propargylic acid, (iso)crotonic acid,aconitic acid, citric acid, isocitric acid, cinnamic acid, and otherbiologically acceptable polymerizable groups, including moleculeslinkable to the backbone polymer which carry one or more of suchpolymerizable groups. Preferably, acrylate-type molecules are used inwhich cross-linking results from carbon-carbon double bonds. Thecross-link density can be varied by variations in the polymer molecularweight, thereby affecting the properties of the gel. A preferredconjugate is acrylated PEG lactate.

The gel can be polymerized by photopolymerization or chemicalpolymerization. Photopolymerization is characteristically initiated byfree radical formation, resulting from photon absorption of certain dyesand chemical compounds to ultimately produce free radicals. Theconjugates are polymerized by exposure of the polymerizable regions tothe generated free radicals. For example, acrylates can be polymerizedusing several initiating systems, for example, Eosin dye, by briefexposure to ultraviolet, long wavelength, or visible light.

Useful photoinitiators are those which can be used to initiate by freeradical generation polymerization of the conjugates without cytotoxicityand within a short time frame, preferably within minutes, and mostpreferably within seconds. Preferred dyes as initiators of choice forlong wavelength ultraviolet or visible light initiation are ethyl Eosin,2,2-dimethoxy-2-phenyl acetophenone, other acetophenone derivatives, andcamphorquinone. Cross-linking and polymerization are initiated amongconjugates by a light-activated free-radical polymerization initiatorsuch as 2,2-dimethoxy-2-phenylacetophenone or a combination of ethylEosin (10⁻¹ to 10⁻² M) and triethanol amine (0.001 to 0.1M), forexample.

The choice of the photoinitiator is largely dependent on thephotopolymerizable regions. When the conjugate includes at least onecarbon-carbon double bond, light absorption by the dye causes the dye toassume an excited state, such as a the triplet state or anion radical.The excited molecule subsequently reacts with the amine to form a freeradical which initiates polymerization. Using such initiators,copolymers may be polymerized in situ ultraviolet light or by visiblelight. Initiation of polymerization is accomplished by irradiation withlight at a wavelength of between about 200-700 nm, preferably in thelong wavelength ultraviolet range or visible range, 320 nm or higher,most preferably about 514 nm or 365 nm.

There are several photo-oxidizable and photo-reducible dyes that may beused to initiate polymerization. These include acridine dyes, e.g.,acriblarine, thiazine dyes such as thionine, xanthine dyes such as rosebengal, and phenazine dyes such as methylene blue. These are used withco-catalyst such as amines, including triethanolamine, sulfur compoundsincluding RSO₂ R¹, heterocycles including imidazole, enolates,organometallics, and other compounds, including N-phenyl glycine. Otherinitiators include camphorquinones and acetophenone derivatives.

Thermal polymerization initiator systems may also be used. Such systemsare unstable at 37° C. and initiate free radical polymerization atphysiological temperatures. Examples include potassium persulfate, withor without tetramethyl ethylenediamine, benzoyl peroxide, with orwithout triethanolamine, and ammonium persulfate with sodium bisulfite.Azo compounds are also used.

Other initiation chemistries may be used besides free radicalinitiation. These include water and amine initiation schemes withisocyanate or isothiocyanate containing conjugates used as thepolymerizable regions.

A bioerodable hydrogel can be formed, for example, byphotopolymerization of aqueous solutions of the poly(hydroxyacid)/polymer conjugates. If the polymer in the conjugates is PEG,preferably the PEG component should be greater than about 40% by weightto provide dispersability on the skin, especially in water-basedformulations.

Polymerization of the end-capped conjugates can occur prior to theirapplication to the skin, or can occur on the skin itself from a solutionso as to form a "mask" on the skin.

The chemical cross-links within the gel are preferably attached tohydrolyticly labile groups, so that the gel can degrade intowater-soluble products, as described in WO 93/17669 by the University ofTexas, Tables 6 and 9. For example, if the conjugate includes PEG whichis reacted at its termini with glycolide to form poly(glycolic acid),and end-capped at all poly(glycolic acid) termini with a polymerizableacrylate group, and the conjugate is gelled, the resulting gel ishydrolytically labile via hydrolysis of the poly(glycolic acid) links.Such a gel will degrade into water-soluble non-toxic products, chieflyPEG, glycolic acid and its oligomers, and oligomers of acrylic acid. Thedegradation rates of the gels can be tailored by appropriate choice ofthe poly(hydroxy acid) such that degradation is substantially completedin times ranging from hours to several months. Shorter times, in therange of hours to days, will often be preferred in cosmeticapplications.

The factors for such tailoring are known to those skilled in the art andare readily adapted to produce the desired rate of hydrolysis. Importantfactors are that esters involving alpha-hydroxy acids generally degradefaster than esters with beta hydroxy acids, which in turn are fasterthan esters with more distantly-substituted acids. This result is aconsequence of the increasing hydrophobicity of more distantlysubstituted acids on the ester bond. Similar shifts are seen whensubstituting other electron-withdrawing groups at the alpha, beta andmore distant positions. A second design factor is that the ester orother linkages degrade faster in the amorphous state, and slower in thecrystalline state, due to the ease of access to the bond by watermolecules. Crystallinity is increased by use of anenantiometrically-pure, single hydroxy acid, such as glycolic acid orL-lactic acid, and decreased by mixtures, such as D,L-lactic acid. Athird factor is pH, with degradation occurring faster at higher pH or atpH's below about 3. Thus, buffering the composition containing thepolymer to a particular pH in the skin-acceptable range, between aboutpH 4 and about pH 9, has a significant effect on the degradation rate ofthe hydroxy acid linkages. The rate of degradation can also beinfluenced by certain conditions of the skin. See, for example, Ali etal., J. Biomedical Materials Res. 27:1409-1418 (1993).

Degradation time should be tailored to the intended application. Forexample, in wart removal, it is preferable to expose the wart to hydroxyacid over a period of days to weeks. Extended periods may also bepreferred, for example, for lightening of age spots. If covered with adressing to prevent removal of the poly(hydroxy acid)/polymer conjugate,a conjugate degrading over a period of about a week to about two weeksmay be appropriate for these uses. A preferred hydroxy acid forincorporation in a conjugate formulation for the latter use is salicylicacid. An alternative hydroxy acid for slow delivery could beenantiometrically pure, such as glycolic acid, with a preferred pH isabout pH 6 to about pH 7. For other applications, for example, to reducethe appearance of wrinkles, it is preferable to expose the wrinkles tohydroxy acid for less than about a day. A preferred formulation for thisuse is D,L-lactic acid, at a slightly alkaline pH, about 7 to about 8.Since the rate of hydrolysis can also be affected by other components inthe formulation, some tailoring of the conjugate composition to theoverall formulation is also preferable. A controlled release of thehydroxy acids from the poly(hydroxy acid)/polymer conjugates can thus beobtained when the conjugate contacts the skin.

Other Components for delivery

Other embodiments include attachment of a physiologically activefunctional molecule or group to an end group, such as to an hydroxy orcarboxy end group of the poly(hydroxy acid)/polymer conjugate. Incertain embodiments, the conjugate has a plurality of hydroxy endgroups, and a physiologically active functional group is attached to atleast one of the hydroxy end groups and additionally a polymerizablegroup, such as acrylate, is attached to at least one of the otherhydroxy end groups. Examples of physiologically active functional groupsinclude fragrances, anti-microbials, including bactericides andfungicides, acne medication, wart removers including salicylic acid withor without other hydroxy acids, reductants to bleach skin spots such ashydroxyquinone, nutrients such as vitamin A, retinoic acid (Retin A) orother vitamins, dyes and sunscreens. Preferred functional molecules orgroups are retinoic acid (Retin A), or other vitamin A derivatives orprecursors. A preferred poly(hydroxy acid)/polymer conjugate to whichthe physiologically active functional group is attached isPEG-lactate-diol.

It may be synthetically useful to attach a physiologically activefunctional group through linkages other than those preferred for use incoupling hydroxy acids, including hydroxyls and carboxyls. In suchcases, a double-bond functionality on the polymer can be directly linkedwith an active derivative, or chemically modified to produce such alinking group, taking advantage of the specific functionalities ofunsaturated groups. See, for example, Larock, R. C., "ComprehensiveOrganic Transformations," New York (1989), at 391. For example, primaryand secondary amines can be added to double bonds. For example, theMichael reaction allows the addition of an active carbanion across adouble bond. See, for example, Merck Index, 10th ed., Merck & Co., N.J.(1983), at p. ONR-60.

The poly(hydroxy acid)/polymer conjugate can have an attachedphysiologically active functional group. The poly(hydroxy acid)/polymerconjugates and the physiologically active functional groups includethose discussed above. The physiologically active functional group ispreferably attached to the conjugate by a covalent linkage, which ispreferably (but not necessarily) spontaneously hydrolyzing on the skinto release the active group. In preferred embodiments, the conjugate hasat least one hydroxy end group and the physiologically active functionalgroup is attached to at least one of the hydroxy end groups. In certainembodiments, the conjugate has a polymerizable group attached to theterminus of one or more of the A_(n) units of the conjugate so as topermit cross-linking between individual poly(hydroxy acid)/polymerconjugates. Preferably, the polymerizable groups are cross-linked so asto form a gel, especially during or after application to the skin. Inother embodiments, some or all of the polymerizable groups are used toattach physiologically active functional groups to the conjugate.

Topical Compositions of Conjugate and Carrier

In most uses, the conjugate will be dispersed in a cosmetic ortherapeutic vehicle. For example, topical cosmetic compositions willinclude an effective amount of the poly(hydroxy acid)/polymer conjugateand a cosmetic agent in a cosmetically acceptable vehicle. When appliedto skin, the requisite amounts of material will depend on the type ofapplication, the duration desired for the effect, and on anycompensation required for penetration into the upper layers of the skin,or the degree of abrasion and shedding of the skin.

The conjugate will be present in the overall formulation in amounts fromabout 0.1% to about 100% by weight, depending on the use of theformulation. In most uses, ranges from about 1% to about 80% arepreferred, and ranges from about 2% to about 50% are more preferred. Inthose uses which require high proportions of hydroxy acid, essentiallypure conjugate, preferably diluted with a few percent of stabilizers,buffers or other ingredients regulating hydrolysis, are preferred. Theconjugates can be end-capped with a polymerizable group, or with abiologically active group.

The conjugates can be in gel form. Preferably, the pH of the formulationwhen applied to the skin is in the range of about 4.0 to about 9.0, andmore preferably is about 5.0 to about 8.5. Preferably, the dosage formis such that it does not substantially deleteriously affect the person.

A pharmaceutically or cosmetically acceptable vehicle can include apowder, lotion, gel, spray, stick, cream, ointment, liquid, emulsion,foam or aerosol. The poly(hydroxy acid)/polymer conjugate can beincorporated into a liquid in dissolved form or colloidal form. Theliquid can be a solvent, partial solvent or non-solvent. In many casesan organic liquid can be used. Preferred solvents or dispersants do notattack the labile ester bonds of the poly(hydroxy acid) during storage.It is therefore preferred that the composition be substantiallyanhydrous during storage, although water and aqueous solutions may bemixed with the active copolymers shortly before application to the skin.

The conjugate can be applied as a powder. It can be applied as a drypowder to moist skin, or as a premoistened powder to dry skin.Preferably, the resultant paste or solution is allowed to dry to form anessentially invisible skin coating. Over a period of time, as discussedabove, the linked poly(hydroxy acid) units gradually hydrolyze toprovide hydroxy acids to the skin. Thus, a controlled release of thehydroxy acids from the conjugate can be obtained when the conjugatecontacts the skin. The solid formulations containing conjugates alsoallow for a substantially uniform application of the hydroxy acids tothe skin, and prevent phase separation of various components which canoccur in formulations which contain polymeric hydroxy acids notconjugated to a backbone polymer.

The composition can include any solid, semi-solid or liquid cosmeticallyand/or physiologically acceptable vehicle, to enable the copolymer to beconveyed to the skin at an appropriate dilution. The nature of thevehicle will depend upon the method chosen for topical administration ofthe composition. The vehicle can itself be inert or it can possessphysiological or pharmaceutical benefits of its own. The selection of avehicle depends on the required product form of the composition.Suitable vehicles can be classified as described herinafter.

Examples of cosmetic agents include emollients, humectants, colorants,pigments, fragrances, moisturizers, viscosity modifiers and any otherconventional cosmetic forming agent. One or more cosmetic agents can beincluded in the cosmetic composition. The form of the cosmeticcomposition can be a powder, lotion, gel, spray, stick, cream, ointment,liquid, emulsion, foam or aerosol. Lists of such materials, andformulations for the creation of particular types of lotions, creams,sunscreens, lipsticks, and other such forms are widely available in thepatent literature and in commercial handbooks, and can be used by thoseskilled in the preparation of such formulations to incorporate the blockcopolymer conjugates described herein. A comprehensive list ofingredients approved or customary for use in cosmetics, toiletries andtopical medications is given in the International Cosmetic IngredientDictionary, Fifth Edition, Vols. 1 & 2, ed. J. A. Wenninger; pub. TheCosmetics, Toiletry and Fragrance Ass'n., Washington, DC 20036-4702.Formulation ingredients used with the copolymers will normally beselected from these ingredients.

To demonstrate the availability of such information, lists offormulation ingredients have been abstracted below from several patents,U.S. Pat. Nos. 4,673,571; 5,158,955; 5,208,355; and 5,244,665; modifiedas appropriate for use with the conjugates described herein.

The ingredients which are usually present in cosmetic compositionsinclude perfumes, coloring agents, pigments, preserving agents,thickening agents, sequestering agents, emulsifying agents, sun filters,fillers, and stabilizing agents. Compositions can also contain variousactive substances such as humectant agents and healing agents.Compositions include treatment creams or lotions for the hands or theface, sunscreen creams, tinted creams, make-up removal milks, foamyliquids for baths, after shave lotions, "eau de toilette", shaving foam,pencils for blush, pencils that may be colored especially for lips, formake-up or for body hygiene or for deodorant compositions.

In listing various classes of materials below by function, it is notedthat individual ingredients may be useful in more than one functionalclass, and that there is some overlap between classes (for example,liquid vehicles with emollients, or humectants with surfactants).

Liquid vehicles

Compositions can include at least one cosmetically acceptable vehicleother than water. Vehicles other than water include solids or liquidssuch as emollients, solvents, humectants, thickeners and powders.Suitable liquid vehicles include mineral oil, silicone oil, lipids (suchas lecithin, vegetable oil, vitamin E, and derivatives of lanolin),low-molecular weight glycols such as PEG-4, PEG-6, propylene glycol,glycerine, and their lower alkyl conjugates, and ketones, such asacetone. Solvents containing unconjugated hydroxyls may undergo slowexchange with the ester groups of the polyhydroxy acids; this may affectthe bulk consistency of the preparation, but would still result in slowrelease of the hydroxy acid monomers. Solvents include ethyl alcohol,isopropanol, ethylene glycol monoethyl ether, diethylene glycolmonobutyl ether, diethylene glycol monoethyl ether, and acetone.

Humectants

Humectants include glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,gelatin, and poly(alkylene oxide)s, such as polyethylene glycol.

Powders

Powders useful alone in dry compositions or as fillers in liquidcompositions include chalk, talc, fullers earth, kaolin, starch, gums,colloidal silicon dioxide, sodium polyacrylate, tetra alkyl and/ortrialkyl aryl ammonium silicate, organically modified montmorilloniteclay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer,and sodium carboxymethyl cellulose.

Creams

Creams can be made with a support that is a soap-based or fattyalcohol-based formula in the presence of an emulsifier. The soaps can beany known in the cosmetic formulation art, and include natural fatty orsynthetic acids having from 12 to 20 carbon atoms (such as lauric acid,myristic acid, palmitic acid, oleic acid, stearic acid and theirmixtures) in concentrations of from 10 to 30% neutralized withcosmetically acceptable salts including sodium, potassium, ammonia,monoethanolamine, triethanolamine and their mixtures.

Gels

Cosmetic gels may contain thickening or gelling agents such as sodiumalginate or arabic gum or cellulose derivatives optionally in thepresence of a solvent. The thickening agent concentration ranges from0.5 to 30 weight percent and preferably ranges from 0.5 to 15 weightpercent. Solvents used can be aliphatic lower alcohols, glycols andtheir ethers with the concentration of the solvents ranging from 2 to20%.

Emollients

Emollients include stearyl alcohol, glyceryl monostearate,propane-1,2-diol, butane-1,3-diol, cetyl alcohol, isopropyl isostearate,stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol,isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetylalcohol, cetyl palmitate, polydimethylsiloxane, di-n-butyl sebacate,isopropyl myristate, isopropyl palmitate, isopropyl stearate, butylstearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil,coconut oil, arachis oil, acetylated lanolin alcohols, petroleum,mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyllinoleate, lauryl lactate, myristyl lactate, decyl oleate, myristylmyristate.

Spray Propellants

Spray compositions may require propellants, including propane, butane,isobutane, carbon dioxide, and nitrous oxide.

Fragrances

The composition can also include a perfume in an amount sufficient tomake the composition acceptable to the consumer and pleasant to use.Usually, the perfume will form from 0.01% to 10% by weight of thecomposition.

Surface Active agents

Surface active agents (detergents) useful in cosmetic compositionsinclude anionic surface active agents, such as salts of fatty acids (forexample, sodium laurate and triethanolamine oleate), alkyl benzenesulfonates (such as triethanolamine dodecyl benzene sulfonate), alkylsulfates such as sodium lauryl sulfate, alkyl ether sulfates,monoglyceride sulfates, isethionates, methyl taurides, acylsarcosinates,acyl peptides, acyl lactylates, polyalkoxylated ether glycollates, forexample trideceth-7 carboxylic acid, and phosphates such as sodiumdilauryl phosphate. Amphoteric surface active agents include imidazolecompounds, N-alkyl amino acids, (such as sodium cocaminopropionate andasparagine derivatives), and betaines. Nonionic surface active agents,such as fatty acid alkanolamides, for example, oleic ethanolamide;esters of polyalcohols, for example Span; polyglycerol esters;polyalkoxylated derivatives, for example TRITON X-100™, polyoxyethylenelauryl ether, and TWEEN™; and amine oxides, such as dodecyl dimethylamine oxides. Cationic surface active agents may be of use in thecomposition. Mixtures of two or more of the above surface active agentscan be employed in the composition. As noted above, many surfactants mayalso be used for their functionality as emollients, humectants orvehicles.

Sunscreen and Oxidation Resistance

The composition may include an effective amount of a sunscreen agent toprovide protection from the harmful effects of excessive exposure tosunlight. This can be particularly important when the skin is partiallydebrided by the application of a hydroxy acid.

Examples of suitable organic sunscreens, when required, includeBenzophenone-3, DEA Methoxycinnamate, Ethyl dihydroxypropyl PABA,Glyceryl PABA, Octyl methoxycinnamate, Octyl salicylate,2-phenyl-benzimidazole-5-sulfonic acid, and Butyl methoxydibenzoylmethane. An inorganic sunscreen, such as titanium dioxide orzinc oxide, can also be used. The sunscreen ingredients may be presentfree in the formulation. The organic sunscreens may also be coupled tothe conjugate block copolymer, as described above.

Anti-aging additives

The composition can also include an additional anti-aging active such asretinol (Vitamin A) and/or derivative thereof, to enhance repair ofphotodamage to skin following exposure to ultra-violet light. Inaddition to retinol itself, examples of derivatives of retinol include:Retinyl acetate, Retinyl butyrate, Retinyl propionate, Retinyloctanoate, Retinyl laurate, Retinyl palmitate, Retinyl oleate, andRetinyl linoleate. The amount of retinol, or a cosmetically acceptablederivative thereof, when present in the composition is from 0.01 to 10%and preferably 0.1 to 5% by weight of the composition. The retinols orderivatives may be coupled to the conjugate.

Oxidation inhibitors

The composition can also include a tocopherol (vitamin E group) as anadditive or as an antioxidant for retinol, or a derivative, when presentin the composition, and to limit oxidative damage to skin. The vitamin Egroup includes alpha-tocopherol, beta-tocopherol, gamma-tocopherol, anddelta-tocopherol. The amount of tocopherol, when present in thecomposition, is from 0.0001 to 50%, preferably from 0.001 to 10% byweight of the composition. The tocopherol may be coupled to theconjugate.

Pigments

Pigments are frequently added to cosmetic formulations to achieve adesired color for application to the skin. Such pigments are known andthe concentrations required to achieve a desired coloring are readilydeterminable. Pigments may be inorganic or organic. Inorganic pigmentsinclude iron oxides (red, black, brown colors), manganese violet,ultramarines (green, blue, pink, red, or violet aluminumsulfosilicates), aquamarines, copper powder, mica, clays, silica, andtitanium dioxide. Organic dyes that have been certified by the US FDAfor cosmetic use generally have the prefix "D&C" and a suffix of a colorand a number (for example, D&C Green #3). There are at least 27 D&Cdyes, each of which may be present as a "lake", i.e., a salt of the dyewith aluminum, zirconium, strontium, barium, calcium, potassium or othermetallic cations, to produce increased adherence to a substrate. InEurope, many of the same colorants, and additional colorants notapproved in the U.S., are listed as "CI" dyes; for example, CI 61570 ischemically the same as D&C Green #5. Each of these pigments may furtherhave several different trade names, or be present in mixed compositions.

Other Additives

The composition can also contain adjuncts other than those alreadymentioned, depending on the form of the intended product. It is, forexample, possible to include antiseptics, preservatives, and coloringagents, which can improve the stability and consumer appeal of thecomposition. Examples of other materials discussed above includeanti-microbials including bactericides and fungicides, ache medication,and wart removers including salicylic acid. Agents known in the art fortreatments of conditions such as blisters, insect bites, diaper rash andcanker sores may be included; these may be include local anesthetics,emollients, and other known materials.

Preservation of the Composition

Examples of methods that can be employed to achieve preservation of thecomposition include sterilization (for example, by filtration or heattreatment); addition of chemical preservatives (such as ethanol, benzoicacid, sodium benzoate, sorbic acid, potassium sorbate, sodium propionateand the methyl, ethyl, propyl and butyl esters of p-hydroxybenzoicacid), generally be from 0.05 to 5%, preferably from 0.1 to 2% byweight; and water activity depression, as by including glycerol,propylene glycol, polyethylene glycol, sorbitol, sugars and salts,sufficient to reduce the water activity from 1 to less than 0.9,preferably to less than 0.85 and most preferably less than 0.8.

Administration of the conjugate formulation

The poly(hydroxy acid)/polymer conjugates is topically applied. Theconjugates can be administered prior to or subsequent to appearance ofthe skin condition. In certain embodiments, the conjugates areadministered to persons who have reached a particular age and whotherefore are more likely to develop one of the skin conditions. Inother embodiments, the conjugates are administered to persons whoexhibit either early or advanced symptoms of the skin condition.

The poly(hydroxy acid)/polymer conjugates are administered in aneffective amount. Examples of alleviating the symptoms of the skinconditions referred to above include treating the condition, curing thecondition, reducing the appearance of the condition, improving theappearance of the condition, creating a pleasing sensation on the skin,modifying the symptoms of the condition, preventing the condition orpreventing worsening of the condition. An effective amount can bedetermined on an individual basis and will be based, at least in part,on consideration of the particular skin condition, on the severity ofthe particular skin condition, on the age of the person receiving theapplication, on the skin sensitivity of the particular person receivingthe application, on the particular poly(hydroxy acid)/polymer conjugateused, on the rate of degradation of the conjugate used, on the vehiclein which the conjugate is in, and on the dose regimen that is employed.An effective amount can be determined by one of ordinary skill in theart employing such factors and using no more than routineexperimentation.

For example, for topical application of acrylated-capped PEG-polylactateconjugates to wrinkled skin, the formulation in a cream form (10%poly(lactate) by weight) is applied to the wrinkled area of skin on aperson. It is then gelled via an included initiator with visible orlong-wavelength UV light. The resulting gel "mask" is allowed to remainin place for one to four hours, after which it is removed. Topicalapplication, one time daily, is continued for four weeks. The skin showsreduction in the appearance of wrinkles. Similar advantageous resultsare obtainable with other poly(hydroxy acid)/polymer conjugates.

In another example, acrylated capped PEG-poly(glycolic acid) conjugateshaving attached hydroxyquinone groups may be topically applied to skinto bleach skin spots. A composition of the conjugates in powder form (6%poly(glycolic acid) by weight) is applied to the area of skin on aperson which has skin spots, two times daily, for three weeks. Similarresults are obtainable with other poly(hydroxy acid)/polymer conjugates,and with other forms of the composition.

Similar beneficial results are obtainable when the formulation isapplied to alleviate the symptoms of dry skin, xerosis, ichthyosis,dandruff, keratoses, melasma, lentigines, blemishes, wrinkles, skinlines, fine lines, oily skin, acne, warts, eczema, pruritic skin,psoriasis, inflammatory dermatoses, disturbed keratinization, brownishspots, age spots, liver spots, pigmented spots, and skin changesassociated with aging.

Product Form and Container

The compositions can be formulated as liquids, for example as a lotion,shampoo, milk or cream for use in conjunction with an applicator such asa rollball applicator, a spray device such as an aerosol can containingpropellant, or a container fitted with a pump to dispense the liquidproduct. For example, a topical skin treatment composition can beformulated as a lotion having a viscosity of from 4,000 to 10,000 mPas,a fluid cream having a viscosity of from 10,000 to 20,000 mPas or acream having a viscosity of from 20,000 to 100,000 mPas, or above. Thecomposition can be packaged in a suitable container to suit itsviscosity and intended use by the customer. Alternatively, thecompositions of the invention can be solid or semi-solid, for examplesticks, powders, creams or gels, for use in conjunction with a suitableapplicator or simply a tube, bottle, or lidded jar, or as aliquid-impregnated fabric, such as a tissue wipe.

EXAMPLES

The present invention will be further understood by reference to thefollowing non-limiting examples of the conjugates and conjugateformulations for topical and cosmetic applications.

Example 1 Synthesis of PEG-Polylactate Conjugates

This example illustrates the synthesis of PEG-polylactate conjugates. 1kg of water-soluble polyethylene glycol (PEG), MW 8 K, wasazeotropically dried by dissolving the polymer in toluene and distillingoff the toluene-water azeotrope under a positive stream of inert gas.The resultant dried solution was cooled to approximately 80° C. and 53.2g of D,L-lactide was charged to the reaction flask. The resultant hotreaction mixture was reheated to boiling and additional toluene wasdistilled off to remove any residual water via the azeotrope. Thereaction was refluxed for approximately 16 hrs and subsequently cooledto approximately 50° C. This warm toluene solution was poured intohexane to precipitate PEG-lactate-diol (PLD), which was collected viafiltration, washed with fresh hexane and mostly dried on the filter witha sufficient stream of inert gas. The damp powder was dried to aconstant weight at 40° C. in a vacuum oven.

Example 2 Synthesis of Capped PEG-Polylactate Conjugates By Acrylation

This example illustrates the synthesis of PEG-polylactate conjugatescapped by acrylation. Solvent-wet PEG-lactate-diol (PLD) prepared as inExample 1 was azeotropically dried by redissolving in toluene anddistilling off the toluene-water azeotrope under a positive stream of aninert gas. The dry toluene solution of PLD was cooled to approximately55° C. and 46.2 g of distilled triethylamine and 25.3 g of distilledacryloyl chloride were added, respectively. After reacting forapproximately 20 min at approximately 50° C., the resultant mixture wasfiltered warm at approximately 40° C. through a medium porosity sinteredglass funnel to remove most of the byproduct salts. The still-warmfiltrate was poured into hexane to precipitate the crude acrylated PLD,which was collected via filtration, washed with fresh hexane, and thenmostly dried on the filter with a sufficient stream of inert gas. Theslightly toluene-wet crude acrylated PLD together with a protectiveamount of hydroquinone (about 25 ppm) was dissolved in fresh warm(approximately 40° C.) toluene, filtered again to remove residual saltsand rapidly passed through a 400 g column of neutral alumina to removeunreacted lactide and other process impurities. A small toluene wash wasemployed and the entire column eluant was collected together with asmall amount (about 150 ppm) of added hydroquinone, which dissolves onwarming. This solution was poured into hexane to precipitate a nearlycolorless solid, which was collected via filtration, washed with freshhexane, and subsequently dried under vacuum at approximately 40° C. to aconstant weight to yield approximately 900 g of purified acrylated PLD,containing a small amount of hydroquinone. The acrylated PLD was foundto contain on average about 3.7±0.5 lactate groups on each end of themolecule.

Example 3 Crosslinking of Acrylated Capped PEG-Polylactate Conjugates

This example illustrates cross-linking by photopolymerization of theacrylated capped PEG-polylactate conjugates prepared in Example 2. Theconjugates were gelled by photopolymerization using free radicalinitiators, with the presence of two acrylic double bonds per chainleading to rapid gelation. A 23% w/w solution of the conjugates in HEPESbuffered saline containing 3 ml of initiator solution (300 mg/ml of2,2-dimethoxy-2-phenylacetophenone in N-vinyl pyrrolidone) was used. 100microliters of the solution were placed on a glass coverslip andirradiated with a low intensity long wavelength UV (LWUV) lamp(Blak-Ray, model 3-100A with flood). The time required for gelation tooccur was approximately 10 seconds.

Example 4 Synthesis of PEG-Lactate and PEG-Lactate Acrylate From HighMolecular Weight PEG

This example illustrates the synthesis of high molecular weightPEG-lactate diol and PEG-lactate acrylate. 40 gm of PEG (MW 20,000) and0.865 g of D,L-lactide were coupled as in Example 1. 30 gm of theproduct was acrylated with 0.299 g triethanolamine and 0.268 g acrylicacid as in Example 2.

Example 5 Synthesis of PEG-Lactate Diol From Low Molecular Weight PEG

This example illustrates the synthesis of low molecular weightPEG-lactate diol. 60 g of PEG-600 NF (MW 600; Union Carbide) wasesterified with 24 g of lactide in the presence of 0.338 g stannousoctanoate in the molten state after azeotropic drying with 50 ml oftoluene. The oily product was recovered from hexane, dissolved intoluene, reprecipitated with hexane, and dried in a round bottom flaskunder vacuum.

Example 6 Synthesis and characterization of F127-(Lactate)-OH, LactylD.P. 10.91

This example illustrates the synthesis and characterization ofF127-(lactate)-OH. 100 g of Pluronic™ F127 poloxamer (BASF) were chargedin a 250 ml Schlenk apparatus and melt dried at 100° C. under vacuum forat least 4 hours. 22.86 g of D,L, lactide (Boehringer Ingelheim, Lot#27689) were added to the melt under a nitrogen atmosphere at 170° C.followed by addition of 0.5 mole % stannous 2-ethylhexanoate (Sigma) toobtain a 200:1 monomer: catalys ratio. The reaction temperature wasmaintained between 170°-180° C. under nitrogen for 4 hours. The reactionproduct melt was allowed to cool to 100° C., then diluted with a 200 mladdition of anhydrous toluene. The cooled reaction mixture wasprecipitated in a large excess of hexane (EM Sciences), collected on acoarse filter and dried to constant weight under vacuum at 40° C. Yield:85 g. The degree of lactyl substitution was 10.91 by NMR. The viscosityof a 10% (w/v) aqueous solution was 14.98 centipoises.

Example 7 Synthesis of PEG-Lactate-Cinnamate

This example illustrates the synthesis of PEG-lactate conjugatesattached to cinnamate, which can be used as a sunscreen.

(I) Synthesis of PEG-Lactate-Diol with Lactate D.P. of 4-5

100 g of polyethylene glycol (MW 8000; Union Carbide, Lot #1s 596679)were charged in a 250 ml Schlenk apparatus and melt dried at 100° C.under vacuum for at least 4 hours. 18.0 g of D,L, lactide (BoehringerIngelheim, Lot #27689) were added to the melt under a nitrogenatmosphere at 170° C. followed by addition of 0.5 mole % stannous2-ethylhexanoate (Sigma, Lot #1554) to obtain a 200:1 ratio of monomerto catalyst. The reaction temperature was maintained between 150°-180°C. under nitrogen for 4 hours. The reaction product melt was allowed tocool to 100° C., then diluted with a 200 ml addition of anhydroustoluene (Aldrich; water content less than 0.0005%). The cooled reactionmixture was precipitated in a large excess of hexane (Omnisolv; EMSciences), collected on a coarse filter and dried to constant weightunder vacuum at 40° C. Yield: 96 g.

(II) Synthesis of PEG Lactate Cinnamate

95 g of PEG-lactate diol were dissolved in 900 mls of anhydrous toluene(Aldrich, Lot #5114) under a nitrogen blanket at 110° C. 150 mls oftoluene were distilled to remove, as the azeotrope, all traces of waterfrom the reaction mixture. The reaction mixture was cooled to 65° C.under a nitrogen flush. Redistilled triethylamine (Amresco, Lot #9078)was added dropwise to the reaction mixture (6.958 ml, a 3x molarexcess). 11.464 g (3 molar excess) of cinnamoyl chloride (Aldrich, Lot#67891) were added under a nitrogen flush. The reaction mixture turnsturbid yellow with the formation of triethylamine hydrochloride. Thereaction mixture was stirred at 65° C. under nitrogen for 12 hours. Thehot reaction mixture was filtered through a 10-15M porosity sinteredglass funnel, and precipitated in a 10 volume excess of hexane (EMSciences). The crude product was collected on a 40-60 porosity sinteredglass funnel. The crude product was redissolved in THF (EM Sciences) at50° C., and filtered through a 10-15M porosity filter. The filtrate waspurified by passing through a packed alumina bed filter (100 g). Theclear filtrate was precipitated in a 10 volume excess of hexane (EMSciences), collected by filtration, and dried in vacuum at 40° C.

Characterization of Cinnamate Derivatives

Yield: 81.6 g dry weight

Lactyl D.P.: 3.98 (NMR, IC)

Cinnamyl D.P.: 2.15 (nominal) (NMR)

Viscosity (10% w/w in deionized water): 13.23

Centipoise: Brookfield Viscometer Model 201

UV-Vis Spectroscopy I_(max) =275 nm: Nicolet UV-Vis Spectrometer 2.0

Critical Micellar Concentration: 4.34% in deionized water: UV-VisSpectrometer, Nicolet; Wyatt Dawn Light Scattering Spectrophotometer.

Example 8 Synthesis and Characterization of PEG-Trimethylene CarbonateConjugates

This example illustrates the synthesis and characterization ofPEG-trimethylene carbonate conjugates. 100 g of polyethylene glycol (MW8000; Union Carbide, Lot #1s596679) were charged to a 250 ml Schlenkapparatus and melt dried at 100° C. under vacuum for at least 4 hours.9.358 g of trimethylene carbonate (Boehringer Ingelheim, Lot #81567)were added to the melt under a nitrogen atmosphere at 180° C. followedby addition of 0.5 mole % (of monomer) of stannous 2-ethylhexanoate(Sigma, Lot #1554). The reaction temperature was maintained between 170°and 190° C. under nitrogen for 4 hours. The reaction product melt wasallowed to cool to 100° C., then diluted with a 200 ml addition ofanhydrous toluene. The cooled reaction mixture was precipitated in alarge excess of hexane (EM Sciences), collected on a coarse filter anddried to constant weight under vacuum at 40° C.

Characterization

Yield: 92.1 g dry weight

Trimethylene Carbonate D.P. 4.16 (NMR: Varian: Gemini 300 MHz)

Viscosity (10% w/w in deionized water) 15.79

Centipoise: (Brookfield Viscometer Model 201)

Example 9 Synthesis of PEG-Caprolactone Conjugates

This example illustrates the synthesis of PEG-caprolactone conjugates.100 g of polyethylene glycol (MW 8000) were heated to 100° C. in apropylene glycol bath. The melted PEG was evacuated to remove moisture,and then blanketed with argon. The evacuation was repeated three times.Vacuum-distilled epsilon-caprolactone (e-CL), 14 mls, was added to themolten PEG. The temperature was increased to 180° C. Stannousethylhexanoate at a 200:1 monomer: catalyst mole ratio ratio wasconstituted in 0.5 mL of anhydrous toluene and added to the reactionmixture. After 4 hours at 180° C., the solution was cooled and dilutedwith 200 mL anhydrous toluene, and then precipitated in a large excessof hexane. The precipitated polymer was dried in a vacuum oven. The dryweight was 96.6 g.

Example 10 Synthesis of PEG-Caprolactone-Acrylate.

This example illustrates the synthesis of PEG-caprolactone conjugatescapped by acrylation. 90 g of the PEG-caprolactone synthesized inExample 9 were added to a 1000 ml three-neck flask. 900 mL of anhydroustoluene were added, and 150 ml of the toluene were distilled off at 110°C. to remove water. The solution was cooled to 60° C. and 8.5 mls oftriethylamine were added, followed by 4.8 ml of acryloyl chloride,dropwise from a piper. After 15 minutes, the reaction mixture wasprecipitated in hexane. The hexane precipitate was recovered on a mediumBuchner funnel and dissolved in THF (tetrahydrofuran) at 40° C. on awater bath. The THF solution was then passed through 90 gm of alumina,prewetted with THF, on a Buchner funnel. The collected filtrate wasevaporated to dryness on a rotary evaporator and placed under vacuumovernight. Yield was about 65 gm.

Example 11 Synthesis of Polyethylene Glycol-Glycolate Conjugates

This example illustrates the synthesis of polyethylene glycol-glycolateconjugates. Commercial polyethylene glycol monomethoxy ether with numberaverage molecular weight 5000 g/mole (PEG 5K) is thoroughly dried at100° C. under a pressure of 10 mm Hg for 16 hr. A 100 ml round bottomflask and a magnetic stir bar are thoroughly flame dried and cooledunder argon. 10 grams of dry PEG 5K monomethoxy ether, 1.16 gram ofglycolide and 10 mg of stannous octanoate are charged under a nitrogenatmosphere into the flask. The reaction mixture is heated in an oil bathat 170° C. for 16 hr under an argon atmosphere. The product is dissolvedin 20 ml methylene chloride and precipitated in 500 ml dry hexane. Thecopolymer is dried in a vacuum oven at 60° C. for 16 hr.

Example 12 Synthesis of Polyethylene Glycol-Glycolate (Trifunctional)Conjugates

This example illustrates the synthesis of polyethylene glycol-glycolate(trifunctional) conjugates. The synthesis is conducted as describedabove in Example 11, but with 10 gram of ethoxylated trimethylolpropanetriol (trifunctional polyethylene glycol with average molecular weight1000 g/mole) and 17.4 grams of glycolide.

Example 13 Synthesis of PEG-(Glycolate)₁ (Caprolactate)₄ Acrylate

This example illustrates the synthesis of PEG-(Glycolate)₁(Caprolactate)₄ acrylate. 100 g of polyethylene glycol, molecular weight8000 g/mole, were dried by azeotroping off the moisture by distillingoff toluene at 110° C. under argon atmosphere. The reaction mixture wasdried further in vacuum at 120° C. for 1 hour to facilitate all removalof toluene. At the end of this drying period, the reaction mixture wasbrought up to 180° C.

Glycolide (Boehringer Ingelheim) was weighed out (2.339 g) in a dry boxunder nitrogen to prevent moisture from being present in the sample intrace amounts. Caprolactone (10.167 ml) was charged to the reactorvessel under nitrogen. Stannous octanoate, used as the catalyst in theratio (1:100), was made up as a stock solution in anhydrous toluene, andadded in a 100 ml quantity. The temperature of the reaction mixture wasmaintained between 180°-190° C., under nitrogen, throughout the reactiontime of 4 hours. At the end of 4 hours, the reaction mixture was cooledto 80°-100° C., and 50 ml of anhydrous toluene (Aldrich) were added,with stirring. The toluene solution was poured into a large excess ofhexane with vigorous vortexing. The precipitated powder was collected byfiltration, and dried under vacuum at 40° C.

The PEG-(Gly)₁ (Cap)₄ -OH obtained from the step above was redissolvedin 1000 ml of anhydrous toluene and 100 ml was distilled toazeotropically removed water. The reaction mixture was cooled to 65° C.under nitrogen. Triethylamine (2 molar excess) was added dropwise to thevigorously swirling reaction mixture. Previously distilled acryloylchloride was added to 2 molar excess under nitrogen flush. Reaction timewas 15 min. The hot reaction mixture was filtered through a mediumporosity Buchner funnel, and precipitated in a large excess of hexane.The crude product was collected by filtration, redissolved inperoxide-free THF (tested for peroxides) and filtered hot through amedium mesh filter. The clear filtrate was filtered through an aluminabed (1:1) and precipitated in a large excess of hexane. The product wascollected by filtration and dried in vacuum. Yield: 82 g.

Example 14 Topical Application of PEG-Polylactate Conjugates

PEG-polylactate, a copolymer of the invention, was made essentially asin Example 1. Volunteers, who were familiar with exfoliants, tested thecopolymer on their skin as follows: The skin of the fingers, or of theforehead, was dampened. Dry copolymer powder was applied to the fingers(and thereby dampened by the applied water) to determine the "feel" ofthe composition. The composition felt very "silky", and dried toinvisibility without becoming tacky. Powder was then applied to thedampened forehead and allowed to dry.

Persistence was assessed by taste. Periodically, a clean, water-dampenedfinger was applied to the forehead and then to the tip of the tongue, todetermine acidity by taste. Initially, there was no acidic taste, butwithin one hour of application an acidic taste was detected. Acid tasteby this method persisted for at least six to eight hours. A comparisontest with a commercial product containing monomeric hydroxy acids("Alpha Hydrox" gel) gave an acid taste only for the first two to fourhours. In addition, the application of the copolymer did not produce anypersistent skin reddening or irritation. The skin was slightly pink fora few minutes just after application, similar to that obtained by theuse of water on the face.

Example 15 Retinoic Acid Conjugates

Retinoic acid was conjugated to PEG lactate diol via a hydrolysableester bond. PEG lactate diol synthesized as in Example 1 (8.1 g) wasazeotropically dried under reduced pressure (3X) using benzene. Thedried PEG lactate diol, retinoic acid (0.90 g) and dimethylaminopyridine(catalytic) were dissolved in 50 mL dichloromethane. The reactionmixture was cooled to 0° C. with an ice bath. Dicylohexylcarbodiimide(0.62 g) in 2 mL of dichloromethane was slowly added. The reactionmixture was stirred for 24 hours (under foil cover), allowing the waterbath to warm up to room temperature. The entire contents of the pot wasdripped into swirling hexane (200 mL) to recover the yellow coloredproduct. The crude product was rinsed twice with 100 mL of diethylether. The air dried crude product was redissolved in tetrahydrofuran(40 mL) and filtered to remove contaminating dicyclohexylurea. Thefiltrate was dripped into swirling hexane (200 mL). The purified productwas recovered in a filter funnel and vacuum dried to yield a yellowsolid (5.8 g).

An alternative approach would be to convert the retinoic acid toretinoyl chloride. The retinoyl chloride can then be used withoutisolation to react with the PEG lactate diol.

Coupling of other materials to the conjugates can readily be achieved byapplication of the procedures described above. For example, attachmentof Eosin Y dye to polyethylene glycol-glycolate conjugates could beachieved as follows. 4.306 gram of polyethylene glycol-glycolateconjugate synthesized in Example 11 are dissolved in 100 ml dryacetone:benzene (1:1) mixture under an argon atmosphere. 0.081 gram ofcarbonyl diimidazole is added to the mixture and the reaction iscontinued at room temperature for 4 hours under argon. 1 gram Eosin Y,dissolved in 10 ml of acetone:benzene (1:1) mixture, is slowly addedinto the reaction mixture. The reaction is continued for 12 hours atroom temperature under argon. The product is separated by repeatedprecipitation from methylene chloride into hexane.

Similarly, the attachment of peptides to polyethylene glycol-glycolideconjugates would be straightforward. 4.306 gram of polyethyleneglycol-glycolide conjugate synthesized in Example 11 are dissolved in100 ml dry DMF. 0.081 gram of carbonyl diimidazole is added to themixture and the activation reaction is continued at room temperature for4 hours under argon atmosphere. 0.301 gram of RGD tripeptide(arginine-glycine-aspartic acid, a biologically active peptide known asa ligand for certain cell receptors) is slowly introduced into thereaction mixture. The reaction is continued for 6 hours and the productis separated by precipitating in a large excess of hexane.

Those skilled in the art will be able to ascertain, using no more thanroutine experimentation, many equivalents of the specific embodiments ofthe invention described herein. These and all other equivalents areintended to be encompassed by the following claims.

We claim:
 1. A method for conditioning skin or alleviating the symptomsof a cosmetic or dermatologic skin condition, the method comprisingtopically applying an effective amount of a composition comprising ahydroxy acid copolymer in combination with a suitable carrier fortopical application to skin in need of treatment thereof, wherein thehydroxy acid copolymer comprises polymerized hydroxy acids covalentlyjoined to a polymer block, and wherein the hydroxy acid copolymer hasthe formula

    PaHb,

wherein P is a hydrophilic polymer block consisting predominantly ofnon-hydroxy acid subunits, H is a polymer block consisting predominantlyof hydroxy acid subunits, a is the number of P blocks, b is the numberof H blocks, a and b are integers of at least one, and the copolymer iseither a linear, brush, star or branched copolymer.
 2. The method ofclaim 1 wherein the sum of a and b is less than about
 100. 3. The methodof claim 1 wherein the linkages between the hydroxy acid subunits andthe polymer backbone are degradable under the conditions present on theskin in the carrier.
 4. The method of claim 1 wherein the hydroxy acidsubunits have a molecular weight of 600 or less.
 5. The method of claim1 wherein the hydroxy acid is selected from the group consisting ofglycolic, lactic, hydroxybutyric, hydroxypentanoic, hydroxyhexanoic,carbonic, glyceric and salicylic.
 6. The method of claim 1 wherein thenumber of hydroxy acid subunits in the hydroxy acid blocks is betweenone and
 100. 7. The method of claim 1 wherein the backbone polymercomprises subunits selected from the group consisting of alkyleneoxides, (meth) acrylates, ethylenes, vinyl alcohols, vinyl acetates,pyrrolidones, oxazolidines, saccharides, amino acids, nucleotides, andphenols.
 8. The method of claim 1 where the backbone polymer is selectedfrom the group consisting of polyalkylene oxide, polyvinyl alcohol,dextran, starch, hyaluronic acid, hydroxyethylcellulose, and polyacrylicacid.
 9. The method of claim 1 wherein the backbone polymer blocks havea molecular weight between 200 and 100,000.
 10. The method of claim 1wherein the skin to be treated is affected with a condition selectedfrom the group consisting of dry skin, xerosis, ichthyosis, dandruff,pigmented spots, keratoses, melasma, lentigines, blemishes, wrinkles,skin lines, oily skin, ache, warts, eczema, pruritic skin, psoriasis,inflammatory dermatoses, disturbed keratinization, and skin changesassociated with aging.
 11. The method of claim 1 wherein the compositionfurther comprises materials selected from the group consisting ofantibiotics, antifungals, pediculicides, antiperspirants, antipruritics,analgesics, anesthetics, blister treatments, canker sore treatments,insect bite treatments, diaper rash treatments, insect repellents, andsunscreens.
 12. The method of claim 1 wherein the carrier is selectedfrom the group consisting of powders, solutions, gels, creams,ointments, sticks, emulsions, foams, aerosols, sprays, and lotions. 13.The method of claim 1 wherein the composition is substantiallyanhydrous.
 14. A method for making a cosmetic composition, comprisingmixing one or more hydroxy acid copolymers in combination with asuitable carrier for topical application to skin wherein the hydroxyacid copolymer comprises polymerized hydroxy acids covalently joined toa polymer block and wherein the hydroxy acid copolymers have the formula

    PaHb,

wherein P is a hydrophilic polymer block consisting predominantly ofnon-hydroxy acid subunits, H is a polymer block consisting predominantlyof hydroxy acid subunits, a is the number of P blocks, b is the numberof H blocks, a and b are integers of at least one, and the copolymer iseither a linear, brush, star or branched copolymer.
 15. The method ofclaim 14 wherein the sum of a and b is less than about
 100. 16. Themethod of claim 14 wherein the linkages between the hydroxy acidsubunits and the polymer backbone are degradable under the conditionspresent on the skin in the carrier.
 17. The method of claim 14 whereinthe hydroxy acid subunits have a molecular weight of 600 or less. 18.The method of claim 14 wherein the hydroxy acid is selected from thegroup consisting of glycolic, lactic, hydroxybutyric, hydroxypentanoic,hydroxyhexanoic, carbonic, glyceric and salicylic.
 19. The method ofclaim 14 wherein the number of hydroxy acid subunits in the hydroxy acidblocks is between one and
 100. 20. The method of claim 14 wherein thebackbone polymer comprises subunits selected from the group consistingof alkylene oxides, (meth) acrylates, ethylenes, vinyl alcohols, vinylacetates, pyrrolidones, oxazolidines, saccharides, amino acids,nucleotides, and phenols.
 21. The method of claim 14 where the backbonepolymer is selected from the group consisting of polyalkylene oxide,polyvinyl alcohol, dextran, starch, hyaluronic acid,hydroxyethylcellulose, and polyacrylic acid.
 22. The method of claim 14wherein the backbone polymer blocks have a molecular weight between 200and 100,000.
 23. The method of claim 14 further comprising adding to thecomposition materials selected from the group consisting of antibiotics,antifungals, pediculicides, antiperspirants, antipruritics, analgesics,anesthetics, blister treatments, canker sore treatments, insect bitetreatments, diaper rash treatments, insect repellents, and sunscreens.24. The method of claim 14 wherein the carrier is selected from thegroup consisting of powders, solutions, gels, creams, ointments, sticks,emulsions, foams, aerosols, sprays, and lotions.
 25. A composition fortreatment of the skin, comprising an effective amount of a compositioncomprising one or more hydroxy acid copolymers in combination with asuitable carrier for topical application to skin in need of treatmentwherein the hydroxy acid copolymer comprises polymerized hydroxy acidscovalently joined to a polymer block, the hydroxy acid copolymer havingthe formula

    PaHb,

wherein P is a hydrophilic polymer block consisting predominantly ofnon-hydroxy acid subunits, H is a polymer block consisting predominantlyof hydroxy acid subunits, a is the number of P blocks, b is the numberof H blocks, a and b are integers of at least one, and the copolymer iseither a linear, brush, star or branched copolymer.
 26. The compositionof claim 25 wherein the sum of a and b is less than about
 100. 27. Thecomposition of claim 25 wherein the linkages between the hydroxy acidsubunits and the polymer backbone are degradable under the conditionspresent on the skin in the carrier.
 28. The composition of claim 25wherein the hydroxy acid subunits have a molecular weight of 600 orless.
 29. The composition of claim 25 wherein the hydroxy acid isselected from the group consisting of glycolic, lactic, hydroxybutyric,hydroxypentanoic, hydroxyhexanoic, carbonic, glyceric and salicylic. 30.The composition of claim 25 wherein the number of hydroxy acid subunitsin the hydroxy acid blocks is between one and
 100. 31. The compositionof claim 25 wherein the backbone polymer comprises subunits selectedfrom the group consisting of alkylene oxides, (meth) acrylates,ethylenes, vinyl alcohols, vinyl acetates, pyrrolidones, oxazolidines,saccharides, amino acids, nucleotides, and phenols.
 32. The compositionof claim 25 where the backbone polymer is selected from the groupconsisting of polyalkylene oxide, polyvinyl alcohol, dextran, starch,hyaluronic acid, hydroxyethylcellulose, and polyacrylic acid.
 33. Thecomposition of claim 25 wherein the backbone polymer blocks have amolecular weight between 200 and 100,000.
 34. The composition of claim25 wherein the composition further comprises materials selected from thegroup consisting of antibiotics, antifungals, pediculicides,antiperspirants, antipruritics, analgesics, anesthetics, blistertreatments, canker sore treatments, insect bite treatments, diaper rashtreatments, insect repellents, and sunscreens.
 35. The composition ofclaim 25 wherein the carrier is selected from the group consisting ofpowders, solutions, gels, creams, ointments, sticks, emulsions, foams,aerosols, sprays, and lotions.
 36. The composition of claim 25 whereinthe composition is substantially anhydrous.